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Carfilzomib or bortezomib in first relapse MM
Introduction
Proteasome inhibitors form the backbone of many reg- imens used to treat multiple myeloma (MM).1 Bortezomib is a boronic acid-based reversible protea- some inhibitor commonly combined with cortico- steroids, alkylating agents, immunomodulatory drugs, or antibodies.2 Peripheral neuropathy is a common cause for treatment discontinuation, although this problem may be mitigated by subcutaneous and once-weekly (instead of bi-weekly) administration.3 Carfilzomib is an epoxyketone drug that binds irreversibly to the protea- some and is approved for the treatment of relapsed myeloma in combination with dexamethasone, or dex- amethasone plus lenalidomide, or daratumumab.4-6 While carfilzomib has limited neurotoxicity, it has been linked to clinically relevant cardiovascular complications, in particular hypertension, heart failure, and renal failure.7 Both bortezomib and carfilzomib predominantly target the b5 subunit of the constitutive proteasome and the immunoproteasome; at higher concentrations they also co-inhibit either b1 and/or b2 subunits with differ- ent inhibition profiles that determine cytotoxicity and may thus be clinically relevant.8
Head-to-head comparison studies of carfilzomib with bortezomib have yielded mixed results. In patients with relapsed or refractory multiple myeloma (RRMM), carfil- zomib was compared to bortezomib, both given with dexamethasone: it was found that carfilzomib improved both progression-free survival (PFS) and overall survival (OS).4,9 In this study (ENDEAVOR), the carfilzomib dose was 56 mg/m2 twice weekly, and patients received treat- ment until progression. In contrast, carfilzomib did not improve PFS, OS, or response rates compared to borte- zomib when given in combination with melphalan and prednisolone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM).10 The carfil- zomib dose used in this trial (CLARION) was 36 mg/m2 twice weekly, and treatment duration was fixed at nine cycles. Similarly, carfilzomib given at a dose of 36 mg/m2 was not superior to bortezomib when given in combina- tion with lenalidomide and dexamethasone for a fixed period (36 weeks) in standard-risk NDMM patients without intention for immediate autologous stem-cell transplantation (ASCT).11 Thus, the optimal choice of proteasome inhibitor, combination, dose and duration of therapy, remains to be established. Superior results seen with carfilzomib in ENDEAVOR indicate a safety profile that lends itself to continuous treatment approaches, suggesting suitability for maintenance. Maintenance with carfilzomib following fixed-duration treatment with cyclophosphamide and dexamethasone in NDMM transplant-ineligible patients has been reported.12 The role of carfilzomib maintenance treatment in patients with RRMM remains unexplored.
Triplet regimens have become standard of care for RRMM in patients who are sufficiently fit and these reg- imens often contain a proteasome inhibitor. The combi- nation of either carfilzomib or bortezomib with dexa- methasone and cyclophosphamide is effective12-14 and economically less challenging than three-drug combina- tions that contain two novel agents. We designed the Myeloma UK five (MUKfive) study, a phase II random- ized, controlled, parallel group, multicenter trial for MM patients at first relapse or refractory to just one treatment
line, with two main objectives. The first was to compare, in a uniform group of patients, the efficacy of carfil- zomib (K) and bortezomib (V), given in combination with cyclophosphamide (C) and dexamethasone (d), i.e., KCd versus VCd, as fixed-duration therapy (24 weeks), in achieving at least very good partial responses (VGPR). The second objective was to evaluate the PFS benefit of maintenance with single-agent carfilzomib in patients responding to KCd.
Methods
The full trial protocol, including eligibility criteria and sample size, have already been published.15 The trial received national research ethics approval from the NHS National Research Ethics Service London, (REC number: 12/LO/1078). Three hun- dred participants were randomized (2:1) to KCd or VCd, using minimization with a random element. KCd participants in at least stable disease after six cycles were randomized (1:1) to receive maintenance carfilzomib or observation. Figure 1 shows the minimization factors and treatment regimens.
The MUKfive trial had two co-primary endpoints: (i) a compar- ison of the induction regimens’ capacity to produce ≥VGPR at 24 weeks after initial randomization (non-inferiority [NI] compari- son with NI margin -5% [difference in proportion]/0.8 [odds ratio; OR], one-sided 5% significance, i.e. 90% confidence inter- val [CI]) and (ii) comparison of maintenance: PFS with mainte- nance treatment (superiority comparison target hazard ratio [HR]=0.67, two-sided 20% significance, i.e. 80% CI)
Secondary endpoints included: neuropathy grade ≥3, or grade ≥2 with pain (induction comparison only); complete responses (CR) and overall response rate (ORR); time to maximum response; duration of response; minimal residual disease (MRD); OS; time to next treatment (TTNT); safety/toxicity; and treatment compliance.
Responses were defined according to International Myeloma Working Group (IMWG) guidelines.16 Safety and toxicity data were graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Flow cytometry to detect MRD was performed as previously report- ed17 with a limit of detection of 10-5, assessing 500,000 cells using six-color antibody combinations. Samples classified as “suspicious” (the sample was likely to be positive but there was insufficient evidence) were designated as not MRD negative.18 Central assessment of genetic risk was performed as previously described,19 supplemented, where appropriate, by local reports that were centrally reviewed. Genetic high risk was defined as at least one of del(17p), gain(1q), or any adverse IgH transloca- tion: t(4;14), t(14;16), or t(14;20).
Total sample sizes of 300 patients for the induction compari- son (200 KCd:100 VCd) and 140 for the maintenance compari- son were required.15 All analyses were pre-planned, unless spec- ified. The analysis population was defined as all participants who received at least one full cycle of allocated chemotherapy. The primary induction endpoint was analyzed using logistic regression, adjusting for minimization factors, with KCd declared non-inferior to VCd if the 90% confidence interval for the odds ratio was above 0.8. PFS, time to maximum response, duration of response, OS and TTNT were analyzed using Kaplan-Meier curves, a log-rank test and Cox proportional haz- ards models, adjusting for minimization factors. Carfilzomib maintenance was declared superior to no maintenance if the PFS hazard ratio was <0.67 and significant at a two-sided 20% level. TTNT was also analyzed using cumulative incidence
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